Many malconditions have in common a trait of excessive cell proliferation. Examples include cancer, Alzheimer's, neurological disorders, psychiatric disorders, and inflammation-related disorders.
The Wee1 protein, a tyrosine kinase, is a mitosis inhibitor. Increasing levels of Wee1 can block cell proliferation. Wee1 levels are low in non-small cell lung cancer. The prostate epithelium has low levels of Wee1, and increasing Wee1 levels in the prostate epithelium can reduce prostate cell proliferation. Wee1 levels are reduced in Alzheimer's patients.
Wee1 can act as a tumor suppressor by inhibiting mitotic entry. Cellular levels of Wee1 are controlled by ubiquitination by E3 ligases and subsequent proteosomic degradation. Cdk1/cyclin B is held in an inactive state during G2 (growth phase) since Wee1 overcomes Cdc25 activity through phosphorylation of Cdk1 at tyrosine 15. As G2 progresses, phosphorylated Wee1 accumulates and is recognized by E3 ubiquitin ligases and is degraded via the proteosome. Cdc25 is then able to remove the inhibitory phosphorylation on Cdk1 and mitotic entry proceeds.
Thus, inhibition of the degradation of Wee1 can provide a route for cell cycle-based therapy of cancer and other malconditions with excessive cell proliferation.